Disulfiram Inhibits Venous Malformation Endothelial Cells: New Use For An Old Drug

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PURPOSE: Venous malformations (VMs) are congenital vascular anomalies with significant morbidity, from coagulopathy to functional limitations and pain, with potential for mortality. Traditional treatment included surgery and interventional procedures, but are rarely curative, and recurrence is common, especially in complex VMs. Postzygotic somatic variants, especially in PIK3CA, in pathogenic endothelial cells, result in overactivity of the PI3K/Akt/mTOR pathway and has become a therapeutic target for pharmacotherapy. This has led to the use of sirolimus, an mTOR inhibitor, for VMs but only resulted in an incomplete response. Previous work in our lab, using high-throughput drug screening, has identified disulfiram (Antabuse) as being superior to sirolimus and alpelisib (an AKT inhibitor) in suppressing vascular malformation endothelial cells (VMECs) at a concentration of 1?M. We hypothesized that disulfiram may have potential as a novel treatment to suppress VMEC growth and a possible therapeutic alternative. METHODS: Human umbilical vein endothelial cells (HUVECs) served as control cells and patient-derived venous malformation endothelial cells (VMECs) were used as the disease model. Cells were cultured at 37C in endothelial cell growth medium and 20% fetal bovine serum and seeded at 5000 cells/well. HUVECs and VMECs were treated with disulfiram at concentrations ranging from 0.10 ?M to 0.01 ?M. After 48 hours incubation, viability was assessed using the WST-8 assay according to manufacturers instructions. Absorbance was measured at 450 nm using a microplate reader. The number of cells at 48 hours was compared to the number of cells present at the start of the experiment. Data were analyzed using a two-way ANOVA (Dunnetts test) to compare the effects of disulfiram on cell viability. Statistical analyses were performed using GraphPad Prism with statistical significance set at p RESULTS: Disulfiram treatment significantly inhibited cell growth in a dose-dependent manner for both HUVECs and VMECs. HUVECs showed a significant inhibition beginning at a concentration of only 0.1 ?M (mean difference = 1.86, p CONCLUSION: This experiment demonstrates that disulfiram effectively inhibits the proliferation of HUVECs and VMECs. Significant inhibition was observed at concentrations as low as 0.1 ?M, with greater effects on proliferation occurring at higher concentrations of 0.5-1 ?M. When clinically used to treat alcohol abuse, plasma concentrations reached an average of 2 ?M. Our results demonstrated significant effects at 1/8th of the dose, suggesting that low-dose disulfiram may suffice in VMs. These results support disulfiram as a potential candidate for therapeutic treatment of vascular malformations in the future. Further studies are underway to elucidate the mechanism by which disulfiram achieves these effects and explore its utility in-vivo.© 2026. Plastic Surgery Research Council | All rights reserved |*Source: https://ps-rc.org/meeting/Program/2026/MS01.cgi*

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